Human T cell leukemia virus type-1 (HTLV-1, hereinafter, abbreviated to HTLV-1, also known as human T lymphotropic virus type-1) is a retrovirus that chronically infects human T cells. It has been known that while a majority of HTLV-1-infected patients are asymptomatic and can live their lives in good health, approximately 3-5% of the infected persons develop an active T-cell malignancy called adult T-cell leukemia (ATL, hereinafter, abbreviated to ATL), and another 0.25-3% of the infected persons develop HTLV-1 associated myelopathy (HAM, hereinafter, abbreviated to HAM)/tropical spastic paraparesis (TSP, hereinafter, abbreviated to TSP) (Non-Patent Documents 1-4).
In some cases, HAM/TSP patients develop chronic inflammatory diseases characterized by multi-organ lymphocytic infiltration, including uveitis, arthritis, polymyositis, Sjogren('s) syndrome, infective dermatitis, alveolitis or the like (Non-Patent Document 5).
It has been reported that in CD4+ CD25+ T cells from the peripheral blood of HAM patients, the expression level of forkhead transcription factor (Foxp3) was lower than those from healthy individuals, T cell proliferation regulatory function of CD4+ CD25+ Foxp3+ T cells (regulatory T cells, abbreviated to Treg) is reduced, and deterioration in Treg function is caused by HTLV-1 Tax gene (Non-Patent Document 6).
It has been reported that CD4+ CD25+ CC-chemokine receptor 4 (CCR4)+ Foxp3 high T cells are increased in the peripheral blood of ATL patients, compared to healthy individuals, whereas CD4+ CD25+ CCR4+ Foxp3 low T cells are increased in the peripheral blood of HAM patients, compared to healthy individuals (Patent Document 1, Non-Patent Document 2). It is also reported that there is a correlation between the number of CD4+ CD25+ CCR4+ Foxp3 low T cells in the peripheral blood, the amount of HTLV-1 provirus, and severity of HAM clinical symptoms (Patent Document 1).
Further, it is also reported that in CD4+ CD25+ CCR4+ cells isolated from HAM patients using anti-human CCR4 antibodies the amount of HTLV-1 viral DNA was increased compared to CD4+ CD25+ CCR4− cells, and interferon-γ (IFN-γ)+ CD4+ CD25+ Foxp3 low T cell is a pathogenic cell of HAM (THAM), and the cell is increased in the peripheral blood of HAM patients (Patent Document 2, Non-Patent Documents 7, 8).
In the clinical treatment of HAM patients, a therapy with steroids such as prednisolone has been conducted as the treatment of chronic inflammation and a therapy with interferon α has been conducted as the anti-viral therapy.
Meanwhile, CC-chemokine receptor 4 (CCR4) is a seven-transmembrane-type membrane protein that expresses on CD4+ T cells, and thymus and activation-regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22 are known as its ligands. CCR4 is known to express on Th2, Th17 and Treg cells.
The known anti-human CCR4 antibodies include anti-human CCR4 chimeric antibody (Non-Patent Document 9) and anti-human CCR4 humanized antibody (Non-Patent Document 10). The anti-human CCR4 humanized antibody (general name: Mogamulizumab, product name: Poteligeo®) was approved for the treatment of relapsed and refractory ATL patients.